Glacera Plus is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both pioglitazone and metformin is appropriate . 

Important Limitations of Use 
Pioglitazone exerts its antihyperglycemic effect only in the presence of endogenous insulin. Glacera Plus should not be used to treat type 1 diabetes or diabetic ketoacidosis, as it would not be effective in these settings. 
Use caution in patients with liver disease .

Recommendations for All Patients 
Glacera Plus should be taken with meals to reduce the gastrointestinal side effects associated with metformin. 
If therapy with a combination tablet containing pioglitazone and metformin is considered appropriate the recommended starting dose is: 
•    15 mg/500 mg twice daily or 15 mg/850 mg once daily and gradually titrated, as needed, after assessing adequacy of therapeutic response and tolerability, 
•    for patients with New York Heart Association (NYHA) Class I or Class II congestive heart failure: 15 mg/500 mg or 15 mg/850 mg once daily and gradually titrated, as needed, after assessing adequacy of therapeutic response and tolerability, 
•    for patients inadequately controlled on metformin monotherapy: 15 mg/500 mg twice daily or 15 mg/850 mg once or twice daily (depending on the dose of metformin already being taken) and gradually titrated, as needed, after assessing adequacy of therapeutic response and tolerability, 
•    for patients inadequately controlled on pioglitazone monotherapy: 15 mg/500 mg twice daily or 15 mg/850 mg once daily and gradually titrated, as needed, after assessing adequacy of therapeutic response and tolerability, 
•    for patients who are changing from combination therapy of pioglitazone plus metformin as separate tablets: Glacera Plus should be taken at doses that are as close as possible to the dose of pioglitazone and metformin already being taken. 

Glacera Plus may be titrated up to a maximum daily dose of 45 mg of pioglitazone and 2550 mg of metformin. 
Metformin doses above 2000 mg may be better tolerated given three times a day. 
After initiation of Glacera Plus or with dose increase, monitor patients carefully for adverse reactions related to fluid retention such as weight gain, edema, and signs and symptoms of congestive heart failure [see Boxed Warning and Warnings and Precautions (5.1)]. Liver tests (serum alanine and aspartate aminotransferases, alkaline phosphatase, and total bilirubin) should be obtained prior to initiating Glacera Plus. Routine periodic monitoring of liver tests during treatment with Glacera Plus is not recommended in patients without liver disease. Patients who have liver test abnormalities prior to initiation of Glacera Plus or who are found to have abnormal liver tests while taking Glacera Plus should be managed as described under Warnings and Precautions .

Recommendations for Use in Renal Impairment 
Assess renal function prior to initiation of Glacera Plus and periodically thereafter. 
Glacera Plus is contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m2. 
Initiation of Glacera Plus in patients with an eGFR between 30 – 45 mL/min/1.73 m2 is not recommended. 
In patients taking Glacera Plus whose eGFR later falls below 45 mL/min/1.73 m2, assess the benefit risk of continuing therapy. 
Discontinue Glacera Plus if the patient’s eGFR later falls below 30 mL/min/1.73 m2 

Concomitant Use with Strong CYP2C8 Inhibitors 
Coadministration of pioglitazone (one of the ingredients in Glacera Plus) and gemfibrozil, a strong CYP2C8 inhibitor, increases pioglitazone exposure approximately 3-fold. Therefore, the maximum recommended dose of Glacera Plus is 15 mg/850 mg daily when used in combination with gemfibrozil or other strong CYP2C8 inhibitors 

Discontinuation for Iodinated Contrast Imaging Procedures 
Discontinue GLACERA PLUS  at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m2; in patients with a history of liver disease, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart Glacera Plus if renal function is stable [see Warnings and Precautions (5.2)].

Congestive Heart Failure Pioglitazone 
Pioglitazone, like other thiazolidinediones, can cause dose-related fluid retention when used alone or in combination with other antidiabetic medications and is most common when pioglitazone is used in combination with insulin. Fluid retention may lead to or exacerbate congestive heart failure. Patients treated with Glacera Plus should be observed for signs and symptoms of congestive heart failure. If congestive heart failure develops, it should be managed according to current standards of care and discontinuation or dose reduction of Glacera Plus must be considered .
Lactic Acidosis Metformin hydrochloride 
Lactic Acidosis 
There have been post-marketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (greater than 5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate:pyruvate ratio;metformin plasma levels generally greater than 5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk. 
If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of Glacera Plus. In Glacera Plus -treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin hydrochloride is dialyzable, with a clearance of up to 170 mL/min under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery. 
Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue Glacera Plus and report these symptoms to their healthcare provider. 
For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below: 
Renal Impairment 
The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney .
•    Before initiating Glacera Plus, obtain an eGFR. 
•    Glacera Plus is contraindicated in patients with an eGFR less than 30mL/min /1.73 m2. Initiation of Glacera Plus is not recommended in patients with eGFR between 30 – 45 mL/min/1.73 m2. 
•    Obtain an eGFR at least annually in all patients taking GLACERA PLUS . In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently. 
•    In patients taking Glacera Plus whose eGFR later falls below 45 mL/min/1.73 m2, assess the benefit and risk of continuing therapy .
Drug Interactions 
The concomitant use of Glacera Plus with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation (e.g. cationic drugs) . Therefore, consider more frequent monitoring of patients. 
Age 65 or Greater 
The risk of metformin-associated lactic acidosis increases with the patient’s age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients . 
Radiological Studies with Contrast 
Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop Glacera Plus at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m2; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart Glacera Plus if renal function is stable. 
Surgery and Other Procedures 
Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension and renal impairment. Glacera Plus should be temporarily discontinued while patients have restricted food and fluid intake. 
Hypoxic States 
Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur, discontinue Glacera Plus. 
Excessive Alcohol Intake 
Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving Glacera Plus. 
Hepatic Impairment 
Patients with hepatic impairment have developed with cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of Glacera Plus in patients with clinical or laboratory evidence of hepatic disease. 

Edema 
In controlled clinical trials with pioglitazone, edema was reported more frequently in patients treated with pioglitazone than in placebo-treated patients and is dose related . In postmarketing experience, reports of new onset or worsening of edema have been received. 
Glacera Plus should be used with caution in patients with edema. Because thiazolidinediones, including pioglitazone, can cause fluid retention, which can exacerbate or lead to congestive heart failure, Glacera Plus should be used with caution in patients at risk for congestive heart failure. Patients treated with Glacera Plus should be monitored for signs and symptoms of congestive heart failure . 

Hypoglycemia 
Patients receiving Glacera Plus in combination with insulin or other antidiabetic medications (particularly insulin secretagogues such as sulfonylureas) may be at risk for hypoglycemia. A reduction in the dose of the concomitant antidiabetic medication may be necessary to reduce the risk of hypoglycemia . Hypoglycemia can also occur when caloric intake is deficient or when strenuous exercise is not compensated by caloric supplement. Elderly, debilitated, or malnourished patients, and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly, and in people who are taking beta-adrenergic blocking drugs.
 
Hepatic Effects 
There have been postmarketing reports of fatal and nonfatal hepatic failure in patients taking pioglitazone, although the reports contain insufficient information necessary to establish the probable cause. There has been no evidence of drug-induced hepatotoxicity in the pioglitazone controlled clinical trial database to date . 
Patients with type 2 diabetes may have fatty liver disease or cardiac disease with episodic congestive heart failure, both of which may cause liver test abnormalities, and they may also have other forms of liver disease, many of which can be treated or managed. Therefore, obtaining a liver test panel (serum alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, and total bilirubin) and assessing the patient is recommended before initiating Glacera Plus therapy. 
In patients with abnormal liver tests, Glacera Plus should be initiated with caution. 
Measure liver tests promptly in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. In this clinical context, if the patient is found to have abnormal liver tests (ALT greater than three times the upper limit of the reference range), Glacera Plus treatment should be interrupted and investigation done to establish the probable cause. Glacera Plus should not be restarted in these patients without another explanation for the liver test abnormalities. 
Patients who have serum ALT greater than three times the reference range with serum total bilirubin greater than two times the reference range without alternative etiologies are at risk for severe drug-induced liver injury, and should not be restarted on Glacera Plus. For patients with lesser elevations of serum ALT or bilirubin and with an alternate probable cause, treatment with Glacera Plus can be used with caution. 

Urinary Bladder Tumors 
Tumors were observed in the urinary bladder of male rats in the two-year carcinogenicity study . In addition, during the three year PROactive clinical trial, 14 patients out of 2605 (0.54%) randomized to pioglitazone and 5 out of 2633 (0.19%) randomized to placebo were diagnosed with bladder cancer. After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were 6 (0.23%) cases on pioglitazone and two (0.08%) cases on placebo. After completion of the trial, a large subset of patients was observed for up to 10 additional years, with little additional exposure to pioglitazone. During the 13 years of both PROactive and observational follow-up, the occurrence of bladder cancer did not differ between patients randomized to pioglitazone or placebo (HR =1.00; [95% CI: 0.59–1.72]). 
Findings regarding the risk of bladder cancer in patients exposed to pioglitazone vary among observational studies; some did not find an increased risk of bladder cancer associated with pioglitazone, while others did. 
A large prospective10-year observational cohort study conducted in the United States found no statistically significant increase in the risk of bladder cancer in diabetic patients ever exposed to pioglitazone, compared to those never exposed to pioglitazone (HR =1.06 [95% CI 0.89–1.26]). 
A retrospective cohort study conducted with data from the United Kingdom found a statistically significant association between ever exposure to pioglitazone and bladder cancer (HR: 1.63; [95% CI: 1.22–2.19]). 
Associations between cumulative dose or cumulative duration of exposure to pioglitazone and bladder cancer were not detected in some studies including the 10year observational study in the U.S., but were in others. Inconsistent findings and limitations inherent in these and other studies preclude conclusive interpretations of the observational data. 
Pioglitazone may be associated with an increase in the risk of urinary bladder tumors. There are insufficient data to determine whether pioglitazone is a tumor promoter for urinary bladder tumors. 
Consequently, Glacera Plus should not be used in patients with active bladder cancer and the benefits of glycemic control versus unknown risks for cancer recurrence with Glacera Plus should be considered in patients with a prior history of bladder cancer. 

Fractures 
In PROactive (the Prospective Pioglitazone Clinical Trial in Macrovascular Events), 5238 patients with type 2 diabetes and a history of macrovascular disease were randomized to pioglitazone (N=2605), force-titrated up to 45 mg daily or placebo (N=2633) in addition to standard of care. During a mean follow-up of 34.5 months, the incidence of bone fracture in females was 5.1% (44/870) for pioglitazone versus 2.5% (23/905) for placebo. This difference was noted after the first year of treatment and persisted during the course of the study. The majority of fractures observed in female patients were nonvertebral fractures including lower limb and distal upper limb. No increase in the incidence of fracture was observed in men treated with pioglitazone (1.7%) versus placebo (2.1%). The risk of fracture should be considered in the care of patients, especially female patients, treated with Glacera Plus and attention should be given to assessing and maintaining bone health according to current standards of care. 

Macular Edema 
Macular edema has been reported in postmarketing experience in diabetic patients who were taking pioglitazone or another thiazolidinedione. Some patients presented with blurred vision or decreased visual acuity, but others were diagnosed on routine ophthalmologic examination.
Most patients had peripheral edema at the time macular edema was diagnosed. Some patients had improvement in their macular edema after discontinuation of the thiazolidinedione. 
Patients with diabetes should have regular eye exams by an ophthalmologist according to current standards of care. Patients with diabetes who report any visual symptoms should be promptly referred to an ophthalmologist, regardless of the patient's underlying medications or other physical findings . 

Vitamin B12 Levels 
In controlled clinical trials of metformin of 29 weeks’ duration, a decrease to subnormal levels of previously normal serum vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on Glacera Plus and any apparent abnormalities should be appropriately investigated and managed. Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. In these patients, routine serum vitamin B12 measurements at two-to three-year intervals may be useful. 

Macrovascular Outcomes 
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Glacera Plus or any other oral antidiabetic drug.

Strong CYP2C8 Inhibitors 
An inhibitor of CYP2C8 (e.g., gemfibrozil) significantly increases the exposure (area under the serum concentration-time curve or AUC) and half-life (t1/2) of pioglitazone. Therefore, the maximum recommended dose of pioglitazone is 15 mg daily if used in combination with gemfibrozil or other strong CYP2C8. 

CYP2C8 Inducers 
An inducer of CYP2C8 (e.g., rifampin) may significantly decrease the exposure (AUC) of pioglitazone. Therefore, if an inducer of CYP2C8 is started or stopped during treatment with pioglitazone, changes in diabetes treatment may be needed based on clinical response without exceeding the maximum recommended daily dose of 45 mg for pioglitazone .

Carbonic Anhydrase Inhibitors 
Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently causes a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with Glacera Plus may increase the risk for lactic acidosis. Consider more frequent monitoring of these patients.. 

Drugs that Reduce Metformin Clearance 
Drugs that are eliminated by renal tubular secretion (e.g., cationic drugs such as cimetidine) have the potential for interaction with metformin by competing for common renal tubular transport systems, and may increase the accumulation of metformin and the risk for lactic acidosis . Consider more frequent monitoring of these patients. 

Alcohol 
Alcohol is known to potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake while receiving Glacera Plus. 

Insulin Secretagogues or Insulin 
If hypoglycemia occurs in a patient coadministered Glacera Plus and an insulin secretagogue (e.g., sulfonylurea), the dose of the insulin secretagogue should be reduced.
If hypoglycemia occurs in a patient coadministered Glacera Plus and insulin, the dose of insulin should be decreased by 10% to 25%. Further adjustments to the insulin dose should be individualized based on glycemic response. 

Drugs Affecting Glycemic Control 
Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid. When such drugs are administered to a patient receiving Glacera Plus, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from a patient receiving Glacera Plus, the patient should be observed closely for hypoglycemia.

For Glacera Plus no preclinical or clinical data on exposed pregnancies or lactation are available.
Women of childbearing potential / Contraception in males and females
Glacera Plus is not recommended in women of childbearing potential not using contraception. If a patient wishes to become pregnant, treatment with Glacera Plus should be discontinued.
Pregnancy
Risk related to pioglitazone
There are no adequate human data from the use of pioglitazone in pregnant women. Animal studies have not shown teratogenic effects but have shown foetotoxicity related to the pharmacologic action (see section 5.3).
Risk related to metformin
Animal studies have not revealed teratogenic effects. Small clinical trials have not revealed metformin to have malformative effects.
Glacera Plus should not be used during pregnancy. If a pregnancy occurs, treatment with Glacera Plus should be discontinued.
Breast-feeding
Both pioglitazone and metformin have been shown to be present in the milk of lactating rats. It is not known whether breast-feeding will lead to exposure of the infant to the medicinal product. Glacera Plus must therefore not be used in women who are breast-feeding (see section 4.3).
Fertility
In animal fertility studies with pioglitazone, there was no effect on copulation, impregnation or fertility index.
Fertility of male or female rats was unaffected by metformin when administered at doses as high as 600 mg/kg/day, which is approximately three times the maximum recommended human daily dose based on body surface area comparisons.
 

Glacera Plus has no or negligible influence on the ability to drive and use machines. However patients who experience visual disturbance should be cautious when driving or using machines.

The following serious adverse reactions are discussed elsewhere in the labeling: 
•    Congestive heart failure [see Boxed Warning and Warnings and Precautions (5.1)] 
•    Lactic acidosis [see Boxed Warning and Warnings and Precautions (5.2)] 
•    Edema [see Warnings and Precautions (5.3)] 
•    Fractures [see Warnings and Precautions (5.7)] 

6.1 Clinical Trials Experience 
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. 
Pioglitazone 
Over 8500 patients with type 2 diabetes have been treated with pioglitazone in randomized, double-blind, controlled clinical trials, including 2605 patients with type 2 diabetes and macrovascular disease treated with pioglitazone from the PROactive clinical trial. In these trials, over 6000 patients have been treated with pioglitazone for six months or longer, over 4500 patients have been treated with pioglitazone for one year or longer, and over 3000 patients have been treated with pioglitazone for at least two years. 
In six pooled 16-to 26-week placebo-controlled monotherapy and 16-to 24-week add-on combination therapy trials, the incidence of withdrawals due to adverse events was 4.5% for patients treated with pioglitazone and 5.8% for comparator-treated patients. The most common adverse events leading to withdrawal were related to inadequate glycemic control, although the incidence of these events was lower (1.5%) with pioglitazone than with placebo (3.0%). 
In the PROactive trial, the incidence of withdrawals due to adverse events was 9.0% for patients treated with pioglitazone and 7.7% for placebo-treated patients. Congestive heart failure was the most common serious adverse event leading to withdrawal occurring in 1.3% of patients treated with pioglitazone and 0.6% of patients treated with placebo. 
Common Adverse Events: 16-to 26-Week Monotherapy Trials 
A summary of the incidence and type of common adverse events reported in three pooled 16-to 26-week placebo-controlled monotherapy trials of pioglitazone is provided in Table 1. Terms that are reported represent those that occurred at an incidence of >5% and more commonly in patients treated with pioglitazone than in patients who received placebo. None of these adverse events were related to the pioglitazone dose.

Common Adverse Events: 16-to 24-Week Add-on Combination Therapy Trials 
A summary of the overall incidence and types of common adverse events reported in trials of pioglitazone add-on to metformin is provided in Table 2. Terms that are reported represent those that occurred at an incidence of >5% and more commonly with the highest tested dose of pioglitazone.

Note: The preferred terms of edema peripheral, generalized edema, pitting edema, and fluid retention were combined to form the aggregate term of “edema.” 
Common Adverse Events: 24-Week GLACERA PLUS  Clinical Trial 
Table 3 summarizes the incidence and types of adverse reactions reported in a controlled, 24-week double-blind clinical trial of GLACERA PLUS  dosed twice daily in patients with inadequate glycemic control on diet and exercise (N=600).

In this 24-week trial, abdominal pain was reported in 2.0% of patients in the GLACERA PLUS  group, 1.6% in the pioglitazone monotherapy group and 3.3% in the metformin monotherapy group. 
Common Adverse Events: PROactive Trial 
A summary of the overall incidence and types of common adverse events reported in the PROactive trial is provided in Table 4. Terms that are reported represent those that occurred at an incidence of >5% and more commonly in patients treated with pioglitazone than in patients who received placebo.

Congestive Heart Failure 
A summary of the incidence of adverse events related to congestive heart failure is provided in Table 5 for the 16-to 24-week add-on to metformin trials. None of the events were fatal.

Cardiovascular Safety 
In the PROactive trial, 5238 patients with type 2 diabetes and a history of macrovascular disease were randomized to pioglitazone (N=2605), force-titrated up to 45 mg daily or placebo (N=2633) in addition to standard of care. Almost all patients (95%) were receiving cardiovascular medications (beta blockers, ACE inhibitors, angiotensin II receptor blockers, calcium channel blockers, nitrates, diuretics, aspirin, statins, and fibrates). At baseline, patients had a mean age of 62 years, mean duration of diabetes of 9.5 years, and mean HbA1c of 8.1%. Mean duration of follow-up was 34.5 months. 
The primary objective of this trial was to examine the effect of pioglitazone on mortality and macrovascular morbidity in patients with type 2 diabetes mellitus who were at high risk for macrovascular events. The primary efficacy variable was the time to the first occurrence of any event in a cardiovascular composite endpoint that included all-cause mortality, nonfatal myocardial infarction (MI) including silent MI, stroke, acute coronary syndrome, cardiac intervention including coronary artery bypass grafting or percutaneous intervention, major leg amputation above the ankle, and bypass surgery

or revascularization in the leg. A total of 514 (19.7%) patients treated with pioglitazone and 572 (21.7%) placebo-treated patients experienced at least one event from the primary composite endpoint (HR 0.90; 95% CI: 0.80, 1.02; p=0.10). 
Although there was no statistically significant difference between pioglitazone and placebo for the three-year incidence of a first event within this composite, there was no increase in mortality or in total macrovascular events with pioglitazone. The number of first occurrences and total individual events contributing to the primary composite endpoint is shown in Table 9.

Weight Gain 
Dose-related weight gain occurs when pioglitazone is used alone or in combination with other antidiabetic medications. The mechanism of weight gain is unclear but probably involves a combination of fluid retention and fat accumulation. 
Tables 10, 11, and 12 summarize the changes in body weight with pioglitazone and placebo in the 16-to 26-week randomized, double-blind monotherapy and 16-to 24week combination add-on therapy trials, the PROactive trial, and the 24-week GLACERA PLUS  trial.

Note: Trial duration of 24 weeks.

Edema 

Edema induced from taking pioglitazone is reversible when pioglitazone is discontinued. The edema usually does not require hospitalization unless there is coexisting congestive heart failure. 
In the 24-week GLACERA PLUS  trial, edema was reported in 3.0% of patients in the GLACERA PLUS  group, 4.2% in the pioglitazone monotherapy group, and 1.4% in the metformin monotherapy group. 
A summary of the frequency and types of edema adverse events occurring in clinical investigations of pioglitazone is provided in Table 13.

Note: The preferred terms of edema peripheral, generalized edema, pitting edema, and fluid retention were combined to form the aggregate term of “edema.”
Hepatic Effects 
There has been no evidence of pioglitazone-induced hepatotoxicity in the pioglitazone controlled clinical trial database to date. One randomized, double-blind, three-year trial comparing pioglitazone to glyburide as add-on to metformin and insulin therapy was specifically designed to evaluate the incidence of serum ALT elevation to greater than three times the upper limit of the reference range, measured every eight weeks for the first 48 weeks of the trial then every 12 weeks thereafter. A total of 3/1051 (0.3%) patients treated with pioglitazone and 9/1046 (0.9%) patients treated with glyburide developed ALT values greater than three times the upper limit of the reference range. None of the patients treated with pioglitazone in the pioglitazone controlled clinical trial database to date have had a serum ALT greater than three times the upper limit of the reference range and a corresponding total bilirubin greater than two times the upper limit of the reference range, a combination predictive of the potential for severe drug-induced liver injury.
Hypoglycemia 
In the pioglitazone clinical trials, adverse events of hypoglycemia were reported based on clinical judgment of the investigators and did not require confirmation with fingerstick glucose testing. 
In the 16-week add-on to sulfonylurea trial, the incidence of reported hypoglycemia was 3.7% with pioglitazone 30 mg and 0.5% with placebo. In the 16-week add-on to insulin trial, the incidence of reported hypoglycemia was 7.9% with pioglitazone 15 mg, 15.4% with pioglitazone 30 mg, and 4.8% with placebo. 
The incidence of reported hypoglycemia was higher with pioglitazone 45 mg compared to pioglitazone 30 mg in both the 24-week add-on to sulfonylurea trial (15.7% versus 13.4%) and in the 24-week add-on to insulin trial (47.8% versus 43.5%). 
Three patients in these four trials were hospitalized due to hypoglycemia. All three patients were receiving pioglitazone 30 mg (0.9%) in the 24-week add-on to insulin trial. An additional 14 patients reported severe hypoglycemia (defined as causing considerable interference with patient’s usual activities) that did not require hospitalization. These patients were receiving pioglitazone 45 mg in combination with sulfonylurea (n=2) or pioglitazone 30 mg or 45 mg in combination with insulin (n=12). 
Urinary Bladder Tumors 
Tumors were observed in the urinary bladder of male rats in the two-year carcinogenicity study [see Nonclinical Toxicology (13.1)]. During the three year PROactive clinical trial, 14 patients out of 2605 (0.54%) randomized to pioglitazone and 5 out of 2633 (0.19%) randomized to placebo were diagnosed with bladder cancer. After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were 6 (0.23%) cases on pioglitazone and two (0.08%) cases on placebo. After completion of the trial, a large subset of patients was observed for up to 10 additional years, with little additional exposure to pioglitazone. During the 13 years of both PROactive and observational follow-up, the occurrence of bladder cancer did not differ between patients randomized to pioglitazone or placebo (HR =1.00; 95% CI: 0.59-1.72) [see Warnings and Precautions (5.6)]. 
Metformin hydrochloride 
In a double-blind clinical study of metformin in patients with type 2 diabetes, a total of 141 patients received metformin therapy (up to 2550 mg per day) and 145 patients received placebo. Adverse reactions reported in greater than 5% of the metformin patients, and that were more common in metformin than placebo-treated patients, are listed in Table 15. In this trial, diarrhea led to discontinuation of study medication in 6% of patients treated with metformin.

Laboratory Abnormalities Hematologic Effects 
Pioglitazone may cause decreases in hemoglobin and hematocrit. In placebo-controlled monotherapy trials, mean hemoglobin values declined by 2% to 4% in patients treated with pioglitazone compared with a mean change in hemoglobin of -1% to +1% in placebo-treated patients. These changes primarily occurred within the first four to 12 weeks of therapy and remained relatively constant thereafter. These changes may be related to increased plasma volume associated with pioglitazone therapy and are not likely to be associated with any clinically significant hematologic effects. 
Vitamin B12 Concentrations 
Metformin may lower serum vitamin B12 concentrations. Measurement of hematologic parameters on an annual basis is advised in patients on GLACERA PLUS  and any apparent abnormalities should be appropriately investigated and managed [see Warnings and Precautions (5.9)]. 
Creatine Phosphokinase 
During protocol-specified measurement of serum creatine phosphokinase (CPK) in pioglitazone clinical trials, an isolated elevation in CPK to greater than 10 times the upper limit of the reference range was noted in nine (0.2%) patients treated with pioglitazone (values of 2150 to 11400 IU/L) and in no comparator-treated patients. Six of these nine patients continued to receive pioglitazone, two patients were noted to have the CPK elevation on the last day of dosing, and one patient discontinued pioglitazone due to the elevation. These elevations resolved without any apparent clinical sequelae. The relationship of these events to pioglitazone therapy is unknown. 
6.2 Postmarketing Experience Pioglitazone 
The following adverse reactions have been identified during post-approval use of pioglitazone. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. 
•    New onset or worsening diabetic macular edema with decreased visual acuity [see Warnings and Precautions (5.8)]. 
•    Fatal and nonfatal hepatic failure [see Warnings and Precautions (5.5)]. Postmarketing reports of congestive heart failure have been reported in patients treated 

with pioglitazone, both with and without previously known heart disease and both with and without concomitant insulin administration. 
In postmarketing experience, there have been reports of unusually rapid increases in weight and increases in excess of that generally observed in clinical trials. Patients who experience such increases should be assessed for fluid accumulation and volume-related events such as excessive edema and congestive heart failure .

Reporting of suspected adverse reactions

- National Pharmacovigilance and Drug Safety Center (NPC)
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Pioglitazone 
During controlled clinical trials, one case of overdose with pioglitazone was reported. A male patient took 120 mg per day for four days, then 180 mg per day for seven days. The patient denied any clinical symptoms during this period. 
In the event of overdosage, appropriate supportive treatment should be initiated according to the patient’s clinical signs and symptoms. 
Metformin hydrochloride 
Overdose of metformin hydrochloride has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin hydrochloride has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases [see Warnings and Precautions (5.2)]. Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated metformin from patients in whom metformin overdosage is suspected.
 

Pioglitazone 
Clinical studies demonstrate that pioglitazone improves insulin sensitivity in insulin-resistant patients. Pioglitazone enhances cellular responsiveness to insulin, increases insulin-dependent glucose disposal and improves hepatic sensitivity to insulin. In patients with type 2 diabetes, the decreased insulin resistance produced by pioglitazone results in lower plasma glucose concentrations, lower plasma insulin concentrations, and lower HbA1c values. In controlled clinical trials, pioglitazone had an additive effect on glycemic control when used in combination with a sulfonylurea, metformin, or insulin [see Clinical Studies (14)]. 
Patients with lipid abnormalities were included in clinical trials with pioglitazone. Overall, patients treated with pioglitazone had mean decreases in serum triglycerides, mean increases in HDL cholesterol, and no consistent mean changes in LDL and total cholesterol. There is no conclusive evidence of macrovascular benefit with pioglitazone or any other antidiabetic medication [see Warnings and Precautions (5.10) and Adverse Reactions (6.1)]. 
In a 26-week, placebo-controlled, dose-ranging monotherapy study, mean serum triglycerides decreased in the 15-mg, 30-mg, and 45-mg pioglitazone dose groups compared to a mean increase in the placebo group. Mean HDL cholesterol increased to a greater extent in patients treated with pioglitazone than in the placebo-treated patients. There were no consistent differences for LDL and total cholesterol in patients treated with pioglitazone compared to placebo (see Table 16).

In the two other monotherapy studies (16 weeks and 24 weeks) and in combination therapy studies with metformin (16 weeks and 24 weeks), the results were generally consistent with the data above.

Absorption 
GLACERA PLUS  
In bioequivalence studies of GLACERA PLUS  15 mg/500 mg and 15 mg/850 mg, the area under the curve (AUC) and maximum concentration (Cmax) of both the pioglitazone and the metformin component following a single dose of the combination tablet were bioequivalent to pioglitazone 15 mg concomitantly administered with Glucophage (500 mg or 850 mg respectively) tablets under fasted conditions in healthy subjects. 
Administration of GLACERA PLUS  15 mg/850 mg with food resulted in no change in overall exposure of pioglitazone. With metformin there was no change in AUC; however, mean peak serum concentration of metformin was decreased by 28% when administered with food. A delayed time to peak serum concentration was observed for both components (1.9 hours for pioglitazone and 0.8 hours for metformin) under fed conditions. These changes are not likely to be clinically significant. 
Pioglitazone 
Following once-daily administration of pioglitazone, steady-state serum concentrations of both pioglitazone and its major active metabolites, M-III (keto derivative of pioglitazone) and M-IV (hydroxyl derivative of pioglitazone), are achieved within seven days. At steady-state, M-III and M-IV reach serum concentrations equal to or greater than that of pioglitazone. At steady-state, in both healthy volunteers and patients with type 2 diabetes, pioglitazone comprises approximately 30% to 50% of the peak total pioglitazone serum concentrations (pioglitazone plus active metabolites) and 20% to 25% of the total AUC. 
Cmax, AUC, and trough serum concentrations (Cmin) for pioglitazone and M-III and M-IV, increased proportionally with administered doses of 15 mg and 30 mg per day. 
Following oral administration of pioglitazone, Tmax of pioglitazone was within two hours. Food delays the Tmax to three to four hours, but does not alter the extent of absorption (AUC). 
Metformin hydrochloride 
The absolute bioavailability of a 500 mg metformin tablet given under fasting conditions is approximately 50% -60%. Studies using single oral doses of metformin tablets of 500 mg to 1500 mg, and 850 mg to 2550 mg, indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination. At usual clinical doses and dosing schedules of metformin, steady-state plasma concentrations of metformin are reached within 24 to 48 hours and are generally <1 mcg/mL. During controlled clinical trials, maximum metformin plasma levels did not exceed 5 mcg/mL, even at maximum doses. 
Food decreases the rate and extent of metformin absorption, as shown by a 40% lower mean Cmax, a 25% lower AUC, and a 35-minute prolongation of Tmax following administration of a single 850 mg tablet of metformin with food, compared to the same tablet strength administered fasting. The clinical relevance of these decreases is unknown. 
Distribution 
Pioglitazone 
The mean apparent volume of distribution (Vd/F) of pioglitazone following single-dose administration is 0.63 ± 0.41 (mean ± SD) L/kg of body weight. Pioglitazone is extensively protein bound (>99%) in human serum, principally to serum albumin.
Pioglitazone also binds to other serum proteins, but with lower affinity. M-III and M-IV are also extensively bound (>98%) to serum albumin. 
Metformin hydrochloride 
The Vd/F of metformin following single oral doses of 850 mg immediate-release metformin averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins. Metformin partitions into erythrocytes, most likely as a function of time. 
Metabolism 
Pioglitazone 
Pioglitazone is extensively metabolized by hydroxylation and oxidation; the metabolites also partly convert to glucuronide or sulfate conjugates. Metabolites M-III and M-IV are the major circulating active metabolites in humans. 
In vitro data demonstrate that multiple CYP isoforms are involved in the metabolism of pioglitazone which include CYP2C8 and, to a lesser degree, CYP3A4 with additional contributions from a variety of other isoforms, including the mainly extrahepatic CYP1A1. In vivo study of pioglitazone in combination with gemfibrozil, a strong CYP2C8 inhibitor, showed that pioglitazone is a CYP2C8 substrate [see Dosage and Administration (2.3) and Drug Interactions (7.1)]. Urinary 6ß-hydroxycortisol/cortisol ratios measured in patients treated with pioglitazone showed that pioglitazone is not a strong CYP3A4 enzyme inducer. 
Metformin hydrochloride 
Intravenous single-dose studies in healthy subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion. 
Excretion and Elimination 
Pioglitazone 
Following oral administration, approximately 15% to 30% of the pioglitazone dose is recovered in the urine. Renal elimination of pioglitazone is negligible and the drug is excreted primarily as metabolites and their conjugates. It is presumed that most of the oral dose is excreted into the bile either unchanged or as metabolites and eliminated in the feces. 
The mean serum half-life (t1/2) of pioglitazone and its metabolites (M-III and M-IV) range from three to seven hours and 16 to 24 hours, respectively. Pioglitazone has an apparent clearance, CL/F, calculated to be five to seven L/hr. 
Metformin hydrochloride 
Renal clearance is approximately 3.5 times greater than creatinine clearance (CLcr), which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination t1/2 of approximately 
6.2 hours. In blood, the elimination t1/2 is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution. 
Specific Populations 
Renal Impairment 
Pioglitazone 
The serum elimination half-life of pioglitazone, M-III and M-IV remains unchanged in patients with moderate (CLcr 30 to 50 mL/min) and severe (CLcr <30 mL/min) renal impairment when compared to subjects with normal renal function. Therefore, no dose adjustment in patients with renal impairment is required.
Metformin hydrochloride 
In patients with decreased renal function (based on eGFR), the plasma and blood t1/2 of metformin is prolonged and the renal clearance is decreased in proportion to the decrease in eGFR [see Dosage and Administration (2.2), Contraindications (4) and Warnings and Precautions (5.2)]. 
Hepatic Impairment 
Pioglitazone 
Compared with healthy controls, subjects with impaired hepatic function (Child-Turcotte-Pugh Grade B/C) have an approximate 45% reduction in pioglitazone and total pioglitazone (pioglitazone, M-III, and M-IV) mean Cmax but no change in the mean AUC values. Therefore, no dose adjustment in patients with hepatic impairment is required. 
There are postmarketing reports of liver failure with pioglitazone and clinical trials have generally excluded patients with serum ALT >2.5 times the upper limit of the reference range. Use GLACERA PLUS  with caution in patients with liver disease [see Warnings and Precautions (5.5)]. 
Metformin hydrochloride 
No pharmacokinetic studies of metformin have been conducted in subjects with hepatic impairment [see Warnings and Precautions (5.5)]. 
Geriatric Patients 
Pioglitazone 
In healthy elderly subjects, Cmax of pioglitazone was not significantly different, but AUC values were approximately 21% higher than those achieved in younger subjects. The mean t1/2 of pioglitazone was also prolonged in elderly subjects (about ten hours) as compared to younger subjects (about seven hours). These changes were not of a magnitude that would be considered clinically relevant. 
Metformin hydrochloride 
Limited data from controlled pharmacokinetic studies of metformin in healthy elderly subjects suggest that total CL/F is decreased, the t1/2 is prolonged, and Cmax is increased, compared to healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function. 
Pediatrics 
Pioglitazone 
Safety and efficacy of pioglitazone in pediatric patients have not been established. GLACERA PLUS  is not recommended for use in pediatric patients [see Use in Specific Populations (8.4)]. 
Metformin hydrochloride 
After administration of a single oral metformin 500 mg tablet with food, geometric mean metformin Cmax and AUC differed less than 5% between pediatric type 2 diabetic patients (12 to 16 years of age) and gender-and weight-matched healthy adults (20 to 45 years of age), and all with normal renal function. 
Gender 
Pioglitazone 
The mean Cmax and AUC values of pioglitazone were increased 20% to 60% in women compared to men. In controlled clinical trials, HbA1c decreases from baseline were generally greater for females than for males (average mean difference in HbA1c 0.5%).
Because therapy should be individualized for each patient to achieve glycemic control, no dose adjustment is recommended based on gender alone. 
Metformin hydrochloride 
Metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 2 diabetes when analyzed according to gender (males=19, females=16). Similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of metformin was comparable in males and females. 
Ethnicity 
Pioglitazone 
Pharmacokinetic data among various ethnic groups are not available. 
Metformin hydrochloride 
No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin in patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (n=249), blacks (n=51), and Hispanics (n=24). 
Drug-Drug Interactions 
Specific pharmacokinetic drug interaction studies with GLACERA PLUS  have not been performed, although such studies have been conducted with the individual pioglitazone and metformin components.

Pioglitazone

Metformin hydrochloride

†AUC = AUC0–∞
‡Ratio of arithmetic means §Metformin hydrochloride extended-release tablets, 500 mg ¶At steady-state with topiramate 100 mg every 12 hours and metformin 500 mg every 12 hours; AUC = AUC0-12h
 

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility GLACERA PLUS  
No animal studies have been conducted with GLACERA PLUS . The following data are based on findings in studies performed with pioglitazone or metformin individually. 
Pioglitazone 
A two-year carcinogenicity study was conducted in male and female rats at oral doses up to 63 mg/kg (approximately 14 times the maximum recommended human oral dose of 45 mg based on mg/m2). Drug-induced tumors were not observed in any organ except for the urinary bladder of male rats. Benign and/or malignant transitional cell neoplasms were observed in male rats at 4 mg/kg/day and above (approximately equal to the maximum recommended human oral dose based on mg/m2). Urinary calculi with subsequent irritation and hyperplasia were postulated as the mechanism for bladder tumors observed in male rats. A two-year mechanistic study in male rats utilizing dietary acidification to reduce calculi formation was completed in 2009. Dietary acidification decreased but did not abolish the hyperplastic changes in the bladder. The presence of calculi exacerbated the hyperplastic response to pioglitazone but was not considered the primary cause of the hyperplastic changes. 
The relevance to humans of the bladder findings in the male rat cannot be excluded. 
A two-year carcinogenicity study was also conducted in male and female mice at oral doses up to 100 mg/kg/day (approximately 11 times the maximum recommended human oral dose based on mg/m2). No drug-induced tumors were observed in any organ. 
Pioglitazone hydrochloride was not mutagenic in a battery of genetic toxicology studies, including the Ames bacterial assay, a mammalian cell forward gene mutation assay (CHO/HPRT and AS52/XPRT), an in vitro cytogenetics assay using CHL cells, an unscheduled DNA synthesis assay, and an in vivo micronucleus assay. 
No adverse effects upon fertility were observed in male and female rats at oral doses up to 40 mg/kg pioglitazone hydrochloride daily prior to and throughout mating and gestation (approximately nine times the maximum recommended human oral dose based on mg/m2). 
Metformin hydrochloride 
Long-term carcinogenicity studies have been performed in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg/day and 1500 mg/kg/day, respectively. These doses are both approximately four times a human daily dose of 2000 mg of the metformin component of GLACERA PLUS  based on body surface area comparisons. No evidence of carcinogenicity with metformin was found in either male or female mice. Similarly, there was no tumorigenic potential observed with metformin in male rats. There was, however, an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/day. 
There was no evidence of mutagenic potential of metformin in the following in vitro tests: Ames test (S. typhimurium), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes). Results in the in vivo mouse micronucleus test were also negative.
Fertility of male or female rats was unaffected by metformin when administered at doses as high as 600 mg/kg/day, which is approximately three times the maximum recommended human daily dose of the metformin component of GLACERA PLUS  based on body surface area comparisons.

13.2 Animal Toxicology and/or Pharmacology 
Heart enlargement has been observed in mice (100 mg/kg), rats (4 mg/kg and above) and dogs (3 mg/kg) treated orally with pioglitazone hydrochloride (approximately 11, one, and two times the maximum recommended human oral dose for mice, rats, and dogs, respectively, based on mg/m2). In a one-year rat study, drug-related early death due to apparent heart dysfunction occurred at an oral dose of 160 mg/kg/day (approximately 35 times the maximum recommended human oral dose based on mg/m2). Heart enlargement was seen in a 13-week study in monkeys at oral doses of 
8.9 mg/kg and above (approximately four times the maximum recommended human oral dose based on mg/m2), but not in a 52-week study at oral doses up to 32 mg/kg (approximately 13 times the maximum recommended human oral dose based on mg/m2).

14 CLINICAL STUDIES 
14.1 Patients Who Have Inadequate Glycemic Control with Diet and Exercise Alone 
In a 24-week, randomized, double-blind clinical trial, 600 patients with type 2 diabetes mellitus inadequately controlled with diet and exercise alone (mean baseline HbA1c 8.7%) were randomized to GLACERA PLUS  15/850 mg, pioglitazone 15 mg, or metformin 850 mg twice daily. Statistically significant improvements in HbA1c and fasting plasma glucose (FPG) were observed in patients treated with GLACERA PLUS  compared to either pioglitazone or metformin alone (see Table 21).

14.2 Patients Previously Treated with Metformin 
The efficacy and safety of pioglitazone as add-on to metformin therapy have been established in two clinical studies. Bioequivalence of GLACERA PLUS  with coadministered pioglitazone and metformin tablets was demonstrated for both GLACERA PLUS  strengths [see Clinical Pharmacology (12.3)]. 
The two clinical trials testing pioglitazone as add-on to metformin therapy included patients with type 2 diabetes on any dose of metformin, either alone or in combination with another antidiabetic agent. All other antidiabetic agents were withdrawn at least three weeks prior to starting study treatment. 
In the first trial, 328 patients were randomized to receive either 30 mg of pioglitazone or placebo once daily for 16 weeks in addition to their current metformin regimen. Treatment with pioglitazone as add-on to metformin produced statistically significant improvements in HbA1c and FPG at endpoint compared to placebo add-on to metformin (see Table 22).

Microcrystalline Cellulose (PH 102)
Croscarmellose Sodium
Povidone (K30) 
Magnesium Stearate
Opadry 03F180011 White 
Purified Water

Not applicable.

Store below 30°C.

Packed in Alu / Alu Blister as 10 tablets per blister and 6 blisters per pack.

Keep all medicine out of reach and sight of children.